An Insulin-to-Insulin Regulatory Network Orchestrates Phenotypic Specificity in Development and Physiology

Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits

Sustainable computational science: the ReScience initiative

Computer science o ers a large set of tools for prototyping, writing, running, testing, validating, sharing and reproducing results, however computational science lags behind. In the best case, authors may provide their source code as a compressed archive and they may feel con dent their research is reproducible. But this is not exactly true. Jonathan Buckheit and David Donoho proposed more than two decades ago that an article about computational results is advertising, not scholarship. e actual scholarship is the full so ware environment, code, and data that produced the result. is implies new work ows, in particular in peer-reviews. Existing journals have been slow to adapt: source codes are rarely requested, hardly ever actually executed to check that they produce the results advertised in the article. ReScience is a peer-reviewed journal that targets computational research and encourages the explicit replication of already published research, promoting new and open-source implementations in order to ensure that the original research can be replicated from its description. To achieve this goal, the whole publishing chain is radically di erent from other traditional scienti c journals. ReScience resides on GitHub where each new implementation of a computational study is made available together with comments, explanations, and so ware tests

The Eps8/IRSp53/VASP Network Differentially Controls Actin Capping and Bundling in Filopodia Formation

There is a body of literature that describes the geometry and the physics of filopodia using either stochastic models or partial differential equations and elasticity and coarse-grained theory. Comparatively, there is a paucity of models focusing on the regulation of the network of proteins that control the formation of different actin structures. Using a combination of in-vivo and in-vitro experiments together with a system of ordinary differential equations, we focused on a small number of well-characterized, interacting molecules involved in actin-dependent filopodia formation: the actin remodeler Eps8, whose capping and bundling activities are a function of its ligands, Abi-1 and IRSp53, respectively; VASP and Capping Protein (CP), which exert antagonistic functions in controlling filament elongation. The model emphasizes the essential role of complexes that contain the membrane deforming protein IRSp53, in the process of filopodia initiation. This model accurately accounted for all observations, including a seemingly paradoxical result whereby genetic removal of Eps8 reduced filopodia in HeLa, but increased them in hippocampal neurons, and generated quantitative predictions, which were experimentally verified. The model further permitted us to explain how filopodia are generated in different cellular contexts, depending on the dynamic interaction established by Eps8, IRSp53 and VASP with actin filaments, thus revealing an unexpected plasticity of the signaling network that governs the multifunctional activities of its components in the formation of filopodia

Competition in the chaperone-client network subordinates cell-cycle entry to growth and stress

© 2019 Moreno et al.The precise coordination of growth and proliferation has a universal prevalence in cell homeostasis. As a prominent property, cell size is modulated by the coordination between these processes in bacterial, yeast, and mammalian cells, but the underlying molecular mechanisms are largely unknown. Here, we show that multifunctional chaperone systems play a concerted and limiting role in cell-cycle entry, specifically driving nuclear accumulation of the G1 Cdk–cyclin complex. Based on these findings, we establish and test a molecular competition model that recapitulates cell-cycle-entry dependence on growth rate. As key predictions at a single-cell level, we show that availability of the Ydj1 chaperone and nuclear accumulation of the G1 cyclin Cln3 are inversely dependent on growth rate and readily respond to changes in protein synthesis and stress conditions that alter protein folding requirements. Thus, chaperone workload would subordinate Start to the biosynthetic machinery and dynamically adjust proliferation to the growth potential of the cell.This work was funded by the Spanish Ministry of Science, Consolider-Ingenio 2010, and the European Union (FEDER) to M Aldea. DF Moreno received an FI fellowship from Generalitat de Catalunya

The effects of an editor serving as one of the reviewers during the peer-review process [version 1; referees:1 approved, 2 approved with reservations]

Background Publishing in scientific journals is one of the most important ways in which scientists disseminate research to their peers and to the wider public. Pre-publication peer review underpins this process, but peer review is subject to various criticisms and is under pressure from growth in the number of scientific publications.   Methods Here we examine an element of the editorial process at eLife, in which the Reviewing Editor usually serves as one of the referees, to see what effect this has on decision times, decision type, and the number of citations. We analysed a dataset of 8,905 research submissions to eLife since June 2012, of which 2,750 were sent for peer review, using R and Python to perform the statistical analysis.   Results The Reviewing Editor serving as one of the peer reviewers results in faster decision times on average, with the time to final decision ten days faster for accepted submissions (n=1,405) and 5 days faster for papers that were rejected after peer review (n=1,099). There was no effect on whether submissions were accepted or rejected, and a very small (but significant) effect on citation rates for published articles where the Reviewing Editor served as one of the peer reviewers.   Conclusions An important aspect of eLife’s peer-review process is shown to be effective, given that decision times are faster when the Reviewing Editor serves as a reviewer. Other journals hoping to improve decision times could consider adopting a similar approach

GANs for Biological Image Synthesis

International audienceIn this paper, we propose a novel application of Generative Adversarial Networks (GAN) to the synthesis of cells imaged by fluorescence microscopy. Compared to natural images, cells tend to have a simpler and more geometric global structure that facilitates image generation. However, the correlation between the spatial pattern of different fluorescent proteins reflects important biological functions, and synthesized images have to capture these relationships to be relevant for biological applications. We adapt GANs to the task at hand and propose new models with casual dependencies between image channels that can generate multi-channel images, which would be impossible to obtain experimentally. We evaluate our approach using two independent techniques and compare it against sensible baselines. Finally, we demonstrate that by interpolating across the latent space we can mimic the known changes in protein localization that occur through time during the cell cycle, allowing us to predict temporal evolution from static images

The effects of an editor serving as one of the reviewers during the peer-review process [version 2; referees: 2 approved, 1 approved with reservations]

Background Publishing in scientific journals is one of the most important ways in which scientists disseminate research to their peers and to the wider public. Pre-publication peer review underpins this process, but peer review is subject to various criticisms and is under pressure from growth in the number of scientific publications.   Methods Here we examine an element of the editorial process at eLife, in which the Reviewing Editor usually serves as one of the referees, to see what effect this has on decision times, decision type, and the number of citations. We analysed a dataset of 8,905 research submissions to eLife since June 2012, of which 2,747 were sent for peer review. This subset of 2747 papers was then analysed in detail.     Results The Reviewing Editor serving as one of the peer reviewers results in faster decision times on average, with the time to final decision ten days faster for accepted submissions (n=1,405) and five days faster for papers that were rejected after peer review (n=1,099). Moreover, editors acting as reviewers had no effect on whether submissions were accepted or rejected, and a very small (but significant) effect on citation rates.   Conclusions An important aspect of eLife’s peer-review process is shown to be effective, given that decision times are faster when the Reviewing Editor serves as a reviewer. Other journals hoping to improve decision times could consider adopting a similar approach

MuSCA: a multi-scale source-sink carbon allocation model to 2 explore carbon allocation in plants. An application on static apple-tree

International audienceBackground and aims : Carbon allocation in plants is usually represented at a topological scale, specific to each model. This makes the results obtained with different models, and the impact of their scales of representation, difficult to compare. In this study, we developed a multi-scale carbon allocation model (MuSCA) that allows the use of different, user-defined, topological scales of a plant, and assessment of the impact of each spatial scale on simulated results and computation time. Methods : Model multi-scale consistency and behaviour were tested on three realistic apple tree structures. Carbon allocation was computed at five scales, spanning from the metamer (the finest scale, used as a reference) up to first-order branches, and for different values of a sap friction coefficient. Fruit dry mass increments were compared across spatial scales and with field data. Key Results : The model was able to represent effects of competition for carbon assimilates on fruit growth. Intermediate friction parameter values provided results that best fitted field data. Fruit growth simulated at the metamer scale differed of ~1 % in respect to results obtained at growth unit scale and up to 60 % in respect to first order branch and fruiting unit scales. Generally, the coarser the spatial scale the more predicted fruit growth diverged from the reference. Coherence in fruit growth across scales was also differentially impacted, depending on the tree structure considered. Decreasing the topological resolution reduced computation time by up to four orders of magnitude. Conclusions : MuSCA revealed that the topological scale has a major influence on the simulation of carbon allocation. This suggests that the scale should be a factor that is carefully evaluated when using a carbon allocation model, or when comparing results produced by different models. Finally, with MuSCA, trade-off between computation time and prediction accuracy can be evaluated by changing topological scales